Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells
Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells
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DOI：
10.1038/sj.onc.1210141
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发表时间：
2007-05-01
期刊：
影响因子：
8
通讯作者：
Taketo, M. M.
中科院分区：
文献类型：
--
作者：
Aoki, K.;Aoki, M.;Taketo, M. M.
结肠腺瘤性息肉病(APC/APC)基因编码一种关键的抑癌基因，其突变激活了β-连环蛋白/T细胞因子(TCF)介导的转录(规范的Wnt信号)。在这里，我们证明了Wnt信号可以导致染色体不稳定(CIN)。作为CIN的一个指标，我们对小鼠息肉和ES细胞的后期桥指数(ABI)进行了评分，在这些细胞中，Wnt信号被APC或β-catenin突变激活。我们发现ABI是野生型对照组的三到九倍。此外，核型分析证实，Wnt信号激活的ES细胞以更高的比率产生新的染色体畸变率，因此CIN。在这些细胞中，显性阴性的TCFs的表达一致地降低了它们的ABI。我们还发现，Wnt信号的激活增加了CDc2(CDK1)的磷酸化，从而抑制了其活性，并在诺可达唑或Colcemid作用下抑制了细胞的凋亡。这些数据表明，Wnt信号刺激细胞逃避有丝分裂停滞和凋亡，导致CIN。在含有核β-连环蛋白的人胃癌组织中，ABI显著高于不含核β-连环蛋白的人胃癌组织。这些结果共同表明，β-连环蛋白/TCF介导的转录本身通过失调G2/M进程而增加CIN。
Adenomatous polyposis coli (APC/Apc) gene encodes a key tumor suppressor whose mutations activate beta-catenin/T-cell factor (TCF)-mediated transcription (canonical Wnt signaling). Here, we show that Wnt signaling can cause chromosomal instability (CIN). As an indicator of CIN, we scored anaphase bridge index (ABI) in mouse polyps and ES cells where Wnt signaling was activated by Apc or beta-catenin mutations. We found three to nine times higher ABI than in wild-type controls. Furthermore, karyotype analysis confirmed that the Wnt signal activated ES cells produced new chromosomal aberrations at higher rates; hence CIN. Consistently, expression of dominant-negative TCFs in these cells reduced their ABI. We also found that Wnt signal activation increased phosphorylation of Cdc2 (Cdk1) that inhibited its activity, and suppressed apoptosis upon exposure of the cells to nocodazole or colcemid. The data suggest that Wnt signaling stimulates the cells to escape from mitotic arrest and apoptosis, resulting in CIN. In human gastric cancer tissues with nuclear beta-catenin, ABI was significantly higher than in those without. These results collectively indicate that beta-catenin/TCF-mediated transcription itself increases CIN through dysregulation of G2/M progression.